3-monosubstituted tropane derivatives as nociceptin receptor ligands

ABSTRACT

Compounds of the formula 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
         R 1  is aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl, all optionally substituted;   R 2  is H; or aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl or alkyl, all optionally substituted;   R 3  is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, all optionally substituted;   X is a bond, —(CH 2 ) m —N(R 7 )—(CH 2 ) n —, —(CH 2 ) m —O—(CH 2 ) n —, —(CH 2 ) m —S—(CH 2 ) n —, —C(O)—, —CH(OH)—, —C(O)N(R 7 )—, —C(O)N(R 7 )-alkylene or —N(R 7 )C(O)—;   R 7  is H or alkyl;   and   m and n are each 0-6, provided that the sum of m and n is 0-6;
 
or a pharmaceutically acceptable salt or solvate thereof, pharmaceutical compositions thereof, and the use of said compounds in the treatment of cough, pain, anxiety, asthma, depression, alcohol abuse, urinary incontinence and overactive bladder are disclosed.

REFERENCE TO PRIORITY APPLICATION

This Application claims the benefit of U.S. Provisional Application Ser.No. 60/731,703, filed Oct. 31, 2005, which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to nociceptin receptor agonist3-monosubstituted tropane derivatives useful in treating cough, pain,anxiety, asthma, alcohol abuse, depression, urinary incontinence oroveractive bladder. Pharmaceutical compositions comprising the compoundsand combinations of the claimed compounds with other agents for treatingcough, allergy or asthma symptoms are also disclosed.

BACKGROUND

Nociceptin is a seventeen amino acid neuropeptide that has been recentlyidentified as a potent endogenous agonist of the opioid-like receptorNOP (previously termed ORL-1). The NOP receptor is a G-protein coupledreceptor with 47% overall homology to the opioid receptors and 64%identical in transmembrane domains. In spite of this homology, classicalopioid ligands have very low affinity for this receptor. Activation ofthe NOP receptor leads to inhibition of adenylyl cyclase activity andmodulation of neuronal K⁺ and Ca⁺² conductance. It is structurallyrelated to the opioid peptides but does not activate opioid receptors.

Nociceptin and its receptor are widely expressed throughout the centralnervous system. Thus, nociceptin is likely to participate in a broadrange of physiological and behavioral functions. Reports in literaturehave implicated its role in cough (see, for example, McLeod et al,Pulmonary Pharmacology & Therapeutics (2002), 15, 213-216) as well as inpain, feeding, locomotor activity, alcohol abuse, urinary incontinence,anxiety, stress, cardiovascular functions, sleep disturbance,Parkinson's Disease and Alzheimer's Disease.

3-Substituted 8-azabicyclo-[3.2.1]octanes were disclosed in U.S. Pat.No. 6,262,066 B1, WO 95/04742, WO 97/48397, and WO 98/25924;3-substituted 8-azabicyclo-[3.2.1]octan-3-ols were disclosed in U.S.Pat. No. 6,727,254 B2.

SUMMARY OF THE INVENTION

Compounds of the present invention are represented by formula I

or a pharmaceutically acceptable salt thereof, wherein

R¹ is R⁴-aryl, R⁴-arylalkyl, R⁴-heteroaryl, R⁴-heteroarylalkyl,R⁴-cycloalkyl, R⁴-cycloalkylalkyl, R⁴-heterocycloalkyl orR⁴-heterocycloalkylalkyl;

R² is R⁵-aryl, R⁵-arylalkyl, R⁵-heteroaryl, R⁵-heteroarylalkyl,R⁵-cycloalkyl, R⁵-cycloalkylalkyl, R⁵-heterocycloalkyl orR⁵-heterocycloalkylalkyl;

R³ is R⁶-alkyl, R⁶-aryl, R⁶-heteroaryl, R⁶-cycloalkyl orR⁶-heterocycloalkyl;

X is a bond, (C₁-C₃)alkylene, —(CH₂)_(m)—N(R⁷)—(CH₂)_(n)—,—(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—, —C(O)—, —CH(OH)—,—C(O)N(R⁷)—, —C(O)N(R⁷)-alkylene or —N(R⁷)C(O)—;

n is 0, 1, 2, 3; 4, 5 or 6; m is 0, 1, 2, 3; 4, 5 or 6; provided thatthe sum of m and n is 0, 1, 2, 3; 4, 5 or 6;

each R⁴ and R⁵ is 1 to 3 substituents independently selected from thegroup consisting of H, halo, alkyl, cycloalkyl, —CN, —CF₃,—(CH₂)_(p)—OR⁸, —N(R¹⁰)₂ and —(CH₂)_(n)—N(R¹⁰)₂;

R⁶ is 1 to 3 substituents independently selected from the groupconsisting of H, halo, alkyl, cycloalkyl, heterocycloalkyl,heterocycloalkylalkyl, —CN, cyanoalkyl, —CF₃, —C(O)alkyl,—(CH₂)_(p)—OR⁸, —COOR⁸, —N(R¹⁰)₂, —(CH₂)_(n)—N(R¹⁰)₂ and —C(O)N(R¹⁰)₂;

p is 0, 1, 2, 3; 4, 5 or 6;

R⁷ is H or alkyl;

R⁸ and R⁹ are independently selected from the group consisting of H,alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, alkyl-C(O)— and alkyl-C(O)—N(R⁷)—C(O)—; and

R¹⁰ is independently selected from the group consisting of H and alkyl.

In another aspect, the invention relates to a pharmaceutical compositioncomprising at least one compound of formula I and a pharmaceuticallyacceptable carrier.

The compounds of the present invention are agonists of the NOP receptor,and therefore, in another aspect, the invention relates to a method oftreating pain, anxiety, cough, asthma, alcohol abuse, depression,urinary incontinence or overactive bladder, comprising administering toa mammal in need of such treatment an effective amount of at least onecompound of formula I.

In another aspect, the invention relates to a method of treating cough,comprising administering to a mammal in need of such treatment aneffective amount of a combination of: (a) at least one compound offormula I; and (b) one or more additional agents for treating cough,allergy or asthma symptoms selected from the group consisting of:antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H₃inhibitors, β-adrenergic receptor agonists, xanthine derivatives,α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives,expectorants, NK₁, NK₂ and NK₃ tachykinin receptor antagonists, andGABA_(B) agonists.

In still another aspect, the invention relates to a pharmaceuticalcomposition comprising at least one compound of formula I and one ormore additional agents selected from the group consisting of:antihistamines, 5-lipoxygenase inhibitors, leukotriene inhibitors, H₃inhibitors, β-adrenergic receptor agonists, xanthine derivatives,α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives,expectorants, NK₁, NK₂ and NK₃ tachykinin receptor antagonists, andGABA_(B) agonists.

In another aspect, the invention relates to a method of treating urinaryincontinence (UI) or overactive bladder comprising administering to amammal in need of such treatment an effective amount of a combinationof: (a) at least one compound of formula I; and (b) one or more agentsuseful for treating UI or overactive bladder.

In still another aspect, the invention relates to a pharmaceuticalcomposition comprising at least one compound of formula I and one ormore agents useful for treating UI or overactive bladder.

DETAILED DESCRIPTION OF THE INVENTION

Referring to formula I, above, preferred compounds of the invention arethose wherein R¹ is R⁴-phenyl and R² is R⁵-phenyl, wherein R⁴ and R⁵ areindependently selected from the group consisting of H, halo and alkyl.More preferably, R¹ is R⁴-phenyl wherein R⁴ is one halo atom, and R² isR⁵-phenyl wherein R⁵ is H or one halo atom. The preferred halo atom forR⁴ and R⁵ is chlorine. The R⁴ and R⁵ substituents are preferably in the2-position in the phenyl ring.

X is preferably a bond, —(CH₂)_(m)—N(R⁷)—(CH₂)_(n)— wherein R⁷ is H, mis 0 and n is 0 or 1, or —C(O)N(R⁷)— wherein R⁷ is H. More preferably, Xis a bond.

R³ is preferably R⁶-aryl, R⁶-heteroaryl or R⁶-heterocycloalkyl, whereinaryl is preferably phenyl, heteroaryl is preferably pyridyl, pyrimidyl,imidazolyl or benzimidazolyl, and heterocycloalkyl is preferablypiperidinyl or morpholinyl. Preferred R⁶ substituents are H, halo,alkyl, OH, —OCH₃ (i.e., —(CH₂)_(n)—OR⁸ wherein n is 0 or 1 and R⁸ is H),hydroxyalkyl (i.e., —(CH₂)_(n)—OR⁸ wherein n is 1 to 6 and R⁸ is H),cycloalkyl and heterocycloalkylalkyl (e.g., piperidinylmethyl). Morepreferably, R⁶ is one substituent selected from H, halo, alkyl, OH and—OCH₃.

Preferred compounds of the invention are those described below inExamples 1, 2, 8, 12, 13, 14, 16, 19, 20, 21, 23, 28, 29 and 62.

A preferred indication for compounds of formula I is the treatment ofcough.

As used herein, the following terms are used as defined below unlessotherwise indicated:

halo represents fluoro, chloro, bromo and iodo;

alkyl (including, for example, the alkyl portions of arylalkyl)represents straight and branched carbon chains and contains from one tosix carbon atoms;

alkylene represents a divalent straight or branched alkyl chain, e.g.,ethylene (—CH₂—)₂ or propylene (—CH₂CH₂CH₂—);

cycloalkyl represents a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 3 to about 7ring atoms. Non-limiting examples of suitable monocyclic cycloalkylsinclude cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalinyl, norbornyl, adamantly and the like;

aryl (including the aryl portion of arylalkyl) represents a carbocyclicgroup containing from 6 to 15 carbon atoms and having at least onearomatic ring (e.g., aryl is a phenyl or naphthyl ring), with allavailable substitutable carbon atoms of the carbocyclic group beingintended as possible points of attachment;

heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclicgroups of 9 to 10 atoms having 1, 2 or 3 heteroatoms independentlyselected from O, S or N, said heteroatom(s) interrupting a carbocyclicring structure and having a sufficient number of delocalized pielectrons to provide aromatic character, provided that the rings do notcontain adjacent oxygen and/or sulfur atoms. Nitrogen atoms can form anN-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyland 4-pyridyl. Typical 6-membered heteroaryl groups are pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxides thereof. Typical5-membered heteroaryl rings are furyl, thienyl, pyrrolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl and isoxazolyl. Bicyclic groupstypically are benzo-fused ring systems derived from the heteroarylgroups named above, e.g. benzimidazolyl, quinolyl, phthalazinyl,quinazolinyl, benzofuranyl, benzothienyl and indolyl. The heteroarylring can be substituted with 1-3 R⁴, R⁵ or R⁶ groups, wherein any of theavailable substitutable carbon or nitrogen atoms in said heteroarylgroup may be optionally and independently substituted;

heterocycloalkyl represents a saturated carbocylic ring containing from3 to 15 carbon atoms, preferably from 4 to 6 carbon atoms, whichcarbocyclic ring is interrupted by 1 to 3 hetero atoms selected from—O—, —S—, —SO—, —SO₂ or —NH—; examples include but are not limited to 2-or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or4-dioxanyl, 1,3-dioxolanyl, 1,3,5-trithianyl, pentamethylene sulfide,perhydroisoquinolinyl, decahydroquinolinyl, trimethylene oxide,azetidinyl, 1-azacycloheptanyl, 1,3-dithianyl, 1,3,5-trioxanyl,morpholinyl, thiomorpholinyl, 1,4-thioxanyl, and1,3,5-hexahydrotriazinyl, thiazolidinyl, tetrahydropyranyl. Theheterocycloalkyl ring can be substituted with 1-3 R⁴, R⁵ or R⁶ groups,wherein any of the available substitutable carbon or nitrogen atoms insaid heterocycloalkyl group may be optionally and independentlysubstituted

Claim 1 does not include compounds known by the skilled artisan to beunstable.

The compounds of the invention can be in purified or isolated form. Theterm “purified”, “in purified form” or “in isolated and purified form”for a compound refers to the physical state of said compound after beingisolated from a synthetic process or natural source or combinationthereof. Thus, the term “purified”, “in purified form” or “in isolatedand purified form” for a compound refers to the physical state of saidcompound after being obtained from a purification process or processesdescribed herein or well known to the skilled artisan, in sufficientpurity to be characterizable by standard analytical techniques describedherein or well known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and Tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

When any variable (e.g., R⁴, etc.) occurs more than one time in anyconstituent or in Formula I, its definition on each occurrence isindependent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of formula I or a pharmaceutically acceptablesalt, hydrate or solvate of the compound contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as,for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyl-oxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di (C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of formula I contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)-ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of formula I incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R″-carbonyl, R″O-carbonyl,NR″R′″-carbonyl where R″ and R′″ are each independently (C₁-C₁₀)alkyl,(C₃-C₇) cycloalkyl, benzyl, or R″-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy (C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217;Anderson et al, The Practice of Medicinal Chemistry (1996), AcademicPress, New York; and in The Orange Book (Food & Drug Administration,Washington, D.C. on their website). These disclosures are incorporatedherein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy groups, in which the non-carbonyl moiety of thecarboxylic acid portion of the ester grouping is selected from straightor branched chain alkyl (for example, acetyl, n-propyl, t-butyl, orn-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (forexample, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (forexample, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

One or more compounds of the invention may also exist as, or optionallyconverted to, a solvate. “Solvate” means a physical association of acompound of this invention with one or more solvent molecules. Thisphysical association involves varying degrees of ionic and covalentbonding, including hydrogen bonding. In certain instances the solvatewill be capable of isolation, for example when one or more solventmolecules are incorporated in the crystal lattice of the crystallinesolid. “Solvate” encompasses both solution-phase and isolatablesolvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

Preparation of Solvates is Generally Known. Thus, for Example, M. Cairaet al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe thepreparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

Compounds of Formula I, and salts, solvates, esters and prodrugsthereof, may exist in their tautomeric form (for example, as an amide orimino ether). All such tautomeric forms are contemplated herein as partof the present invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). Individualstereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other, or other selected, stereoisomers. Thechiral centers of the present invention can have the S or Rconfiguration as defined by the IUPAC 1974 Recommendations. The use ofthe terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates, esters and prodrugs of the compounds of Formula I, areintended to be included in the present invention.

Compounds of the invention can be prepared by known methods fromstarting materials either known in the art or prepared by methods knownin the art. Scheme 1 shows a typical reaction scheme for preparingcompounds of formula I wherein R¹ and R² are as defined above, X is abond and R^(3a) is R⁶-phenyl or R⁶-heteroaryl joined to the tropane ringthrough a ring carbon (e.g., R⁶—(2-pyrimidyl) or R⁶-pyridyl).

Compounds of formula I in Scheme 1 wherein R^(3a) is pyridinyl can beconverted to the corresponding piperidinyl compounds by hydrogenationwith an agent such as PtO₂.

Scheme 2 shows a typical reaction scheme for preparing compounds offormula I wherein R¹ and R² are as defined above, X is a bond and R^(3b)is R⁶-heteroaryl or R⁶-heterocycloalkyl joined to the tropane ringthrough a ring nitrogen (e.g., R⁶—(pyrazol-1-yl) or R⁶-piperidinyl). Themesylate intermediate is also used to prepare compounds of formula Iwherein R¹ and R² are as defined above, X is —N(R⁷)—(CH₂)_(n)— whereinR⁷ is H and n is 0, and R^(3c) is, for example, R⁶-pyridyl orR⁶-pyrimidyl, where the pyridyl or pyrimidyl ring is joined through aring carbon atom. Also, the tropane alcohol intermediate can beconverted to the compound wherein X is —O— and R^(3d) is R⁶-phenyl orR^(3e) is R⁶-pyrimidyl; the amino-tropane intermediate can be convertedto a compound wherein —X—R³ is —NHC(O)—R³, which can be reduced toobtain the corresponding —NH—CH₂—R³ compound.

Scheme 3 shows a typical reaction scheme for preparing compounds offormula I wherein R¹, R² and R³ are as defined above and X is—C(O)N(R⁷)—, which can be reduced to compounds wherein X is —CH₂—N(R⁷)—.

Scheme 4 shows a reaction scheme for preparing compounds of formula Iwherein R¹ and R² are as defined above, X is a bond, and R³ isbenzimidazolyl.

The starting materials used in the above procedures are commerciallyavailable or procedures for making them are known in the art.

The following solvents and reagents are referred to herein by theabbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol(MeOH); N,N-dicyclo-hexylcarbodiimide (DCC); dichloroethane (DCE); ethylacetate (EtOAc); lithium diisopropyl amide (LDA); triethylamine (Et₃N)and N,N-dimethylformamide (DMF); diisobutylaluminum hydride (DIBAL);hydroxybenzotriazole (HOBT);1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI);4-dimethylaminopyridine (DMAP); diisopropylethylamine (DIPEA);methanesulfonyl (mesyl, Ms); sodium bis(trimethylsilyl)amide (NaHMDS);thin layer chromatography (TLC). Room temperature is abbreviated as rt.

EXAMPLE 1

Step 1:

NaBH₄ (1.5 g, 39.82 mmol) was added to a solution of2,2′-dichlorobenzo-phenone 1 (5 g, 19.9 mmol) in MeOH (40 ml) at rt.After stirring at rt for 2 h, the mixture was quenched with H₂O,neutralized with 1N HCl followed by evaporation of MeOH. The residue wasextracted with EtOAc, washed with brine, dried (MgSO₄) and concentratedto give the desired compound 2 (5 g) as white solid which was used fornext step reaction without purification. ¹H NMR (CDCl₃) δ 7.45 (m, 4H),7.35 (m, 4H), 6.60 (d, 1H), 2.58 (d, 1H, OH).

Step 2:

The product of Step 1 (20.36 g, 80.47 mmol) in CH₂Cl₂ was treated withSOBr₂ (30.11 g, 144.85 mmol) at 0° C. After stirring at rt overnight,the mixture was quenched with ice and NaHCO₃ (aq.), extracted withCH₂Cl₂, dried, filtered and concentrated to produce the desired compound3 (23.6 g). ¹H NMR (CDCl₃) δ 7.6 (d, 2H), 7.4 (d, 2H), 7.13 (m, 4H), 7.0(s, 1H).

Step 3:

A solution of tropinone (10 g, 71.84 mmol) in DCE (200 ml) was addedα-chloroethyl chloroformate (15.4 g, 108 mmol) dropwise at 0° C. Themixture was then heated at reflux for 2 h. Solvent was evaporated togive a brown residue. The residue was dissolved in MeOH (200 ml) andheated at reflux for 2 h. The MeOH was evaporated to give a solid whichwas stirred in EtOAc, filtered and washed with ether to give the desiredcompound 4 (7 g). Crude product was used for the next step withoutfurther purification. ¹H NMR (CDCl₃) δ 4.45 (s, br, 2H), 3.35 (dd, 2H),2.58 (d, 2H), 2.49 (dd, 2H), 2.0 (m, 2H).

Step 4:

A mixture of 4 (26 g, 161 mmol), 3 (53 g, 168 mmol) and K₂CO₃ (110 g,796 mmol) in anhydrous CH₃CN (410 ml) was heated at 80° C. Reactionprogress was monitored by ¹H NMR analysis. ˜79% conversion was observedafter 87 h. The reaction mixture was cooled to rt, diluted with CH₂Cl₂,filtered and concentrated. Purification of the residue by SiO₂chromatography (4-7% EtOAc/hexane) gave the desired compound 5. ¹H NMR(CDCl₃) δ 7.9 (d, 2H), 7.3 (m, 4H), 7.2 (m, 2H), 5.7 (s, 1H), 3.35 (s,br, 2H), 2.7 (dd, 2H), 2.3 (m, 2H), 2.2 (d, 2H), 1.65 (dd, 2H).

Step 5:

Potassium tert-butoxide (232 g) was added slowly to a stirred solutionof 5 (300 g) and tosylmethyl isocyanide (211 g) in anhydrous1,2-dimethoxyethane (3.5 l) and absolute EtOH (240 ml) under N₂ at −40°C. The mixture was slowly warmed to rt and stirred at rt overnight. Themixture was filtered and washed with EtOAc. Most of the solvent in thefiltrate was evaporated in vacuo (bath temperature <40° C.) to give asuspension which was filtered and washed with ether to give 6 (158 g).LC/ESI-MS m/z=371 (C₂₁H₂₀Cl₂N₂.H⁺).

Step 6:

LDA was freshly generated from diisopropyl amine (2.27 ml, 16.15 mmol)and n-BuLi (2.5 M, 6.46 ml, 16.15 mmol) in THF (25 ml). The LDA solutionwas treated with a solution of 6 in THF (25 ml) dropwise at −40° C.,stirred for 2 h and 2-chloro-pyrimidine (1.85 g, 16.15 mmol) was added.The mixture was slowly warmed to rt, stirred at rt overnight, quenchedwith water, extracted with EtOAc, dried (MgSO₄) and concentrated.Purification of the residue by SiO₂ chromatography (1:4 EtOAc/hexane)gave 7 (3 g). LC/ESI-MS m/z=449 (C₂₅H₂₂Cl₂N₄. H⁺).

Step 7:

A mixture of 7 (200 mg) and conc. HCl (2 ml) was heated at 100° C. in asealed tube for 3 days, cooled to 0° C., neutralized with aqueous NaOHsolution, extracted with EtOAc, dried (MgSO₄) and concentrated.Purification of the residue by SiO₂ chromatography (0-50% EtOAc/hexane)gave the title compound (110 mg). LC/ESI-MS m/z=424 (C₂₄H₂₃Cl₂N₃.H⁺).

EXAMPLES 2 AND 3

Step 1:

To a stirred solution of 6 (20 g, 53.9 mmol) in THF (100 ml) was addedNaHMDS/THF (40.4 ml, 2M) dropwise at −78° C. under N₂. The solution wasstirred at −78° C. for ˜1 hr, then 2-bromopyridine (17 g, 154 mmol) inTHF was added dropwise. After stirring for another hour at thistemperature, the reaction flask was moved to a CH₃CN/dry ice bath. Thereaction mixture was slowly warmed to rt, stirred at rt overnight,quenched with sat. aq. NH₄Cl at −78° C., warmed to rt, and extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and evaporated to dryness. The residue was washed with etherseveral times to give the desired compound 8 (19.1 g) which was used inthe next reaction without further purification. LC/ESI-MS: m/z 448(C₂₆H₂₃Cl₂N₃. H⁺).

Step 2:

A mixture of 8 (5 g), NaOH (20 g), and ethylene glycol (40 ml) wasstirred and heated to 200° C. under N₂ atmosphere for two to three days.After the reaction was complete, the mixture was cooled to rt anddissolved in 1 N HCl solution. The suspension was partitioned withCH₂Cl₂ under basic conditions. The organic layer was dried over Na₂SO₄,filtered, and evaporated to dryness. Purification of the residue by SiO₂chromatography (EtOAc/hexane) gave Example 2 (˜4.3 g), LC/ESI-MS: m/z423 (C₂₅H₂₄Cl₂N₂.H⁺) and Example 3, LC/ESI-MS: m/z 423 (C₂₅H₂₄Cl₂N₂.H⁺).

EXAMPLES 4 AND 5

Step 1:

Compound 9 was prepared according to the procedure described in Example2, Step 1, using 6, NaHMDS and 2-bromo-3-methylpyridine. LC/ESI-MS: m/z462 (C₂₇H₂₅Cl₂N₃.H⁺).

Step 2:

To a stirred solution of 9 (1.92 g, 4.156 mmol) in THF was added 1 MLiALH₄/THF solution (4.57 ml, 4.57 mmol) dropwise at rt under N₂. Themixture was stirred at 50° C. for 1 h. After cooling to rt, thefollowing solutions were added sequentially: 190 μl water, 570 μl 15%NaOH, and 190 μl water. The mixture was stirred, filtered, andevaporated to dryness. Purification of the residue by SiO₂chromatography (EtOAc/hexane) gave Example 4 (˜370 mg), LC/ESI-MS: m/z437 (C₂₆H₂₆Cl₂N₂.H⁺) and Example 5, LC/ESI-MS: m/z 437 (C₂₆H₂₆Cl₂N₂.H⁺).

EXAMPLES 6 AND 7

Step 1:

Compound 10 was prepared according to the procedure described in Example2, Step 1, using 6, NaHMDS and 2,5-dibromopyridine. LC/ESI-MS m/z=528(C₂₆H₂₂BrCl₂N₃.H⁺).

Step 2:

A mixture of 10 (210 mg) and conc. HCl (1.5 ml) was heated at 100° C. ina sealed tube for 3 days, cooled to rt, neutralized with aqueous NaOHsolution, extracted with EtOAc, dried (MgSO₄) and concentrated.Purification of the residue by SiO₂ chromatography (0-50% EtOAc/hexane)gave Example 6, LC/ESI-MS m/z=503 (C₂₅H₂₃BrCl₂N₂.H⁺) and Example 7,LC/ESI-MS: m/z 503 (C₂₅H₂₃BrCl₂N₂.H⁺).

EXAMPLE 8

Step 1:

Compound 11 was prepared according to the procedure described in Example2, Step 1, using 6, NaHMDS and 2-bromo-6-methoxypyridine. LC/ESI-MS: m/z478 (C₂₇H₂₅Cl₂N₃O.H⁺).

Step 2:

To a stirred solution of 11 (21 mg, 0.044 mmol) in THF, was added 1 MLiALH₄/THF solution (132 μl, 0.132 mmol) dropwise at 0° C. under N₂. Themixture was stirred at 60° C. overnight. After cooling to rt, thefollowing solutions were added sequentially: 2 μl water, 6 μl 15% NaOH,and 2 μl water. The mixture was stirred, filtered, and evaporated todryness. Purification of the residue by SiO₂ chromatography (0-40%EtOAc/hexane) gave the title compound (5 mg). ESI-MS: m/z 453(C₂₆H₂₆Cl₂N₂O.H⁺).

EXAMPLE 9

Step 1:

To a stirred solution of 6 (371 mg, 1 mmol) in THF was added NaHMD/THF(750 μl, 2M) dropwise at −78° C. under N₂. The solution was stirred at−78° C. for ˜0.5 hr, and then 2,6-difluoropyridine in THF was addeddropwise. After stirring for at least 6 h at this temperature, thereaction mixture was slowly warmed to rt, and stirred over the weekend.The mixture was cooled to −78° C., quenched with sat. aq. NH₄Cl, warmedto rt and partitioned between aq. NH₄Cl solution and EtOAc-hexane (1:1).The combined organic layers were dried over Na₂SO₄, filtered, andevaporated to dryness. Purification of the residue by SiO₂chromatography gave 12 (194 mg). LC/ESI-MS: m/z 466 (C₂₆H₂₂Cl₂FN₃.H⁺).

Step 2:

To a stirred solution of 12 (69.5 mg, 0.149 mmol) in THF was added 1 MLiAlH₄/THF solution (149 μl, 0.149 mmol) dropwise at rt under N₂. Themixture was stirred at rt overnight. The following solutions were addedsequentially: 5 μl water, 15 μl 15% NaOH, and 5 μl water. The mixturewas stirred, filtered, and evaporated to dryness. Purification of theresidue by SiO₂ chromatography (0-100% EtOAc/hexane) gave the titlecompound (14 mg). LC/ESI-MS: m/z 441 (C₂₅H₂₃Cl₂FN₂.H⁺).

EXAMPLES 10 AND 11

Step 1:

To a stirred solution of 6 (3336 mg, 9 mmol) in THF was added NaHMDS/THF(6750 μl, 2M, 13.5 mmol) dropwise at −78° C. under N₂. The solution wasstirred at −78° C. for ˜0.5 h, and then 2-bromo-5-fluoropyridine (5000mg, 28.4 mmol) in THF was added dropwise. After stirring for at least 8h at this temperature, the reaction mixture was slowly warmed to rt andstirred overnight. The mixture was cooled to −78° C., quenched with sat.aq. NH₄Cl, warmed to rt and partitioned between aq. NH₄Cl solution andEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andevaporated to dryness. Purification of the residue by SiO₂chromatography (EtOAc/hexane) gave 13 (1650 mg). ESI-MS: m/z 466(C₂₆H₂₂Cl₂FN₃, H⁺).

Step 2:

A mixture of 13 (67 mg), NaOH (400 mg), and ethylene glycol (4 ml) in asealed tube was stirred and heated to 150° C. overnight. After coolingto rt, the mixture was added to H₂O and EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, filtered, and evaporated todryness. Purification of the residue by SiO₂ chromatography (0-100%EtOAc/hexane) gave Example 10 (˜2 mg), ESI-MS: m/z 441 (C₂₅H₂₃Cl₂FN₂.H⁺)and Example 11 (5 mg), LC/ESI-MS: m/z 439 (C₂₅H₂₄Cl₂N₂O.H⁺).

EXAMPLE 12

Step 1:

A mixture of 2-bromo-3-methylpyridine (1114 μl, 10 mmol), NBS (1780 mg,10 mmol), and benzoyl peroxide (45 mg) in CCl₄ was refluxed for 3 h.After cooling to rt, the suspension was filtered. Purification of theresidue by SiO₂ chromatography (EtOAc/hexane) gave the desired compound(600 mg). ESI-MS: m/z 250, 252, and 254 (C₆H₅Br₂N.H⁺)

Step 2:

To a solution of the product of Step 1 (595 mg, 2.36 mmol) in DMF wasadded piperidine (205 mg, 2.4 mmol) and K₂CO₃ (979 mg, 7.08 mmol),sequentially. The mixture was stirred at rt overnight, quenched withice-water and then partitioned with ether. The organic layer was driedover Na₂SO₄, filtered, and concentrated. Purification of the residue bySiO₂ chromatography (0-50% EtOAc/hexane) gave the desired compound (˜450mg). C₁₁H₁₅BrN₂, LC/ESI-MS: m/z 255 and 257 (C₁₁H₁₅BrN₂.H⁺)

Step 3:

Compound 14 was prepared according to the procedure described in Example2, Step 1, using 6, NaHMDS and the product of Step 2. LC/ESI-MS: m/z 545(C₃₂H₃₄Cl₂N₄.H⁺).

Step 4:

14 and LiAlH₄ were used according to the procedure described in Example9, Step 2, to obtain the title compound. LC/ESI-MS: m/z 520(C₃₁H₃₅Cl₂N₃.H⁺).

EXAMPLE 13

Step 1:

To a mixture of 6 (580 mg) and fluorobenzene (˜1.5 ml) was addedpotassium bis(trimethylsilyl)amide (580 mg) in fluorobenzene (˜2.5 ml)under N₂. The mixture was stirred for 10 min, then heated in a microwaveat 100° C. for 18 min. After cooling to rt, the mixture was quenchedwith saturated aq. NH₄Cl and partitioned with EtOAc. The organic layerwas dried over Na₂SO₄, filtered, and concentrated. The residue waswashed with ether to give 15 (˜450 mg). LC/ESI-MS: m/z 447(C₂₇H₂₄Cl₂N₂).

Step 2:

To a stirred solution of 15 (310 mg, 0.693 mmol) in THF was added 1 MLiALH₄/THF solution (693 μl, 0.693 mmol) dropwise at rt under N₂. Themixture was warmed to 60° C. and stirred overnight. The followingsolutions were added sequentially: 50 μl water, 150 μl 15% NaOH, and50111 water. The mixture was stirred, filtered, and evaporated todryness. Purification of the residue by SiO₂ chromatography (0-50%EtOAc/hexane) gave the title compound (˜80 mg). LC/ESI-MS: m/z 422(C₂₆H₂₅Cl₂N.H⁺).

EXAMPLE 14

Step 1:

Compound 16 was prepared according to the procedure described in Example1, Step 4, using 4,1-chloro-2-(chlorophenylmethyl)benzene and K₂CO₃. ¹HNMR (CDCl₃) δ 7.95 (d, 1H), 7.55 (d, 2H), 7.2 (m, 5H), 7.05 (t, 1H),5.25 (s, 1H), 3.4 (s, b, 2H), 2.65 (d, b, 2H), 2.1 (d, b, 4H), 1.75 (m,2H).

Step 2:

Compound 17 was prepared according to the procedure of Example 1, Step5, using 16, potassium tert-butoxide and tosylmethyl isocyanide. ¹H NMR(CDCl₃) δ 7.9 (d, 1H), 7.45 (d, 2H), 7.25 (m, 5H), 7.05 (t, 1H), 5.0 (s,1H), 3.15 (s, b, 2H), 2.7 (m, 1H), 2 (m, 4H), 1.65 (m, 2H), 1.25 (d,2H).

Step 3:

Compound 18 was prepared according to the procedure of Example 2, Step1, using 17, NaHMDS and 2-bromopyridine. LC/ESI-MS: m/z 414(C₂₆H₂₄ClN₃.H⁺).

Step 4:

The procedure of Example 6, Step 2, was used with 18 and conc. HCl togive the title compound. LC/ESI-MS: m/z 389. (C₂₅H₂₅ClN₂.H⁺).

EXAMPLE 15

Step 1:

Compound 20 was prepared according to the procedure of Example 1, Step5, using 19, tosylmethyl isocyanide and potassium tert-butoxide inanhydrous 1,2-dimethoxyethane and absolute EtOH. ESI-MS: m/z 339(C₂₁H₂₀F₂N₂.H⁺).

Step 2:

Compound 21 was prepared according to the procedure of Example 2, Step1, using 20, NaHMDS and 2-bromopyridine in THF. ESI-MS: m/z 416(C₂₆H₂₃F₂N₃.H⁺).

Step 3:

Using the procedure of Example 2, Step 2, with 21 and NaOH in ethyleneglycol, the title compound was prepared. LC/ESI-MS m/z=391(C₂₅H₂₄F₂N₂.H⁺)

EXAMPLE 16

Step 1:

A solution of 6 (2 g) was added to DIBAL/toluene (7.5 ml, 1.5 M) at 0°C. The mixture was slowly warmed to rt and then stirred at 50° C. for 3h, quenched with MeOH and H₂O at 0° C., filtered, extracted with EtOAc,dried (MgSO₄), filtered and concentrated. Purification of the residue bySiO₂ chromatography (5% EtOAc/hexane) gave 22. ¹H NMR (CDCl₃) δ 9.6 (s,1H), 7.75, d, 2H), 7.2 (m, 4H), 7.1 (t, 2H), 5.4 (s, 1H), 3.1 (s, br,1H), 2.5 (m, 1H), 2.2 (m, 2H), 1.75 (t, 2H), 1.5 (m, 4H). LC/ESI-MSm/z=374 (C₂₁H₂₁Cl₂NO.H⁺)

Step 2:

To a solution of 22 (410 mg) in EtOH was added 1,2-diaminobenzene (119mg) and NaHSO₃ (2.3 ml, 40% in H₂O). The mixture was stirred at refluxfor 3 h, concentrated, then partitioned between CH₂Cl₂ and water. TheCH₂Cl₂ solution was dried (MgSO₄), filtered and concentrated.Purification of the residue by SiO₂ chromatography gave the titlecompound. LC/ESI-MS m/z=462 (C₂₇H₂₅Cl₂N₃.H⁺)

EXAMPLE 17

Step 1:

Compound 6 (1 g) was dissolved in conc. HCl and then kept at 0° C. for 3days. The solution was then heated to 80° C. for 2 h, cooled to rt, andevaporated to dryness. Water was added and the solution was adjusted topH 7 using 1 N NaOH solution. The aqueous solution was partitioned withEtOAc. The organic layer was dried over Na₂SO₄, filtered, andconcentrated to give 23 (970 mg), which was directly used in the nextstep. ESI-MS: m/z 390 (C₂₁H₂₁Cl₂NO₂.H⁺).

Step 2:

To a solution of 23 (21.5 mg, 0.055 mmol) in DMF at rt was added EDCI(15.9 mg, 0.0827 mmol) and HOBT (10.4 mg, 0.077 mmol) in DMF and aniline(5.6 mg, 0.06 mmol) in DMF. Et₃N (26 μl, 0.187 mmol) was then added. Thereaction mixture was stirred at rt overnight. Water and EtOAc were addedto the reaction mixture. The organic layer was dried over Na₂SO₄,filtered, and concentrated. Purification of the residue by SiO₂chromatography gave the title compound (11.2 mg). LC/ESI-MS: m/z 465(C₂₇H₂₆Cl₂N₂O.H⁺).

EXAMPLE 18

To a mixture of 23 (118 mg, 0.303 mmol) and 2-aminopyridine (55 mg, 0.58mmol) in anhydrous CH₂Cl₂ was added EDCI (118 mg, 0.76 mmol) and DMAP(15 mg, 0.123 mmol) at rt under N₂. The reaction mixture was stirred atrt overnight. The solvent was evaporated in vacuo, and ether and waterwere added to the residue. The organic layer was dried over Na₂SO₄,filtered and concentrated. Purification of the residue by SiO₂chromatography gave the title compound (97 mg). LC/ESI-MS: m/z 466(C₂₆H₂₅Cl₂N₃O.H⁺).

EXAMPLE 19

PtO₂ (40 mg) was added to a solution of Example 2 (200 mg) in CH₂Cl₂.The mixture was stirred at rt under 1 atm H₂ environment through aballoon for ˜24 h, filtered and concentrated. Purification of theresidue by SiO₂ chromatography gave the title compound (˜190 mg).LC/ESI-MS: m/z 429 (C₂₅H₃₀Cl₂N₂.H⁺).

EXAMPLE 20

A suspension of Example 19 (30 mg) in formic acid (100 μl) and 37% aq.formaldehyde (200 μl) was stirred and heated at 70° C. for ˜7 h. Themixture was evaporated to dryness, and then distributed to EtOAc and 1 NNaOH solution. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Purification of the residue by SiO₂ chromatography gavethe title compound (17.8 mg). LC/ESI-MS: m/z 443 (C₂₆H₃₂Cl₂N₂.H⁺).

EXAMPLE 21

A mixture of Example 19 (55 mg, 0.128 mmol) and K₂CO₃ (53 mg, 0.385mmol) in DMF was stirred at rt for 20 min, and then bromoacetonitrile(17.8 μl, 0.256 mmol) was added. The mixture was stirred at rt for 30min and then heated at 60° C. overnight. The mixture was cooled to rt,quenched with water, extracted with ether, dried over MgSO₄, filteredand concentrated. Recrystallization of the residue gave the titlecompound (16 mg). LC/ESI-MS: m/z 468 (C₂₇H₃₁Cl₂N₃.H⁺).

EXAMPLE 22

Step 1:

To a stirred solution of 5 (5 g) in MeOH (200 ml) was added NaBH₄ (0.7g) at 0° C. The mixture was stirred at 0° C. for 2 h. The MeOH wasevaporated and the resultant residue was treated with aqueous NH₄Cl,extracted with EtOAc, dried (MgSO₄), filtered and concentrated.Purification of the residue by SiO₂ chromatography gave compound 24(2.54 g), LC/ESI-MS: m/z 362 (C₂₀H₂₁Cl₂NO.H⁺) and compound 25 (1.71 g),LC/ESI-MS: m/z 362 (C₂₀H₂₁Cl₂NO.H⁺).

Step 2:

To a stirred solution of 24 (1.38 g) in CH₂Cl₂ (35 ml) was added Et₃N(0.64 ml) and CH₃SO₂Cl (0.36 ml) at 0° C. The mixture was stirred at 0°C. for 3.5 h, quenched with water, extracted with CH₂Cl₂, dried(Na₂SO₄), filtered and concentrated to give 26. LC/ESI-MS: m/z=440(C₂₁H₂₃Cl₂NO₃S.H⁺). The crude product was used in the next reactionwithout further purification.

Step 3:

To a solution of 26 (286 mg) in DMF (3 ml) was added NaH (60% in mineraloil, 39 mg) at 0° C. The mixture was stirred at 0° C. for 10 min.,warmed to rt, then pyrazole was added and the mixture stirred at 60° C.overnight. The reaction was quenched with aqueous NH₄Cl, and the mixtureextracted with EtOAc, dried over Na₂SO₄, and purified by preparative TLCto give the title compound. LC/ESI-MS: m/z=412 (C₂₃H₂₃Cl₂N₃.H⁺).

EXAMPLE 23

The title compound was prepared according to the procedure of Example22, Step 3, using 26 and imidazole. ESI-MS: m/z=412 (C₂₃H₂₃Cl₂N₃.H⁺).

EXAMPLES 24 AND 25

A mixture of the title compounds was prepared according to the procedureof Example 22, Step 3, using 26 and 1,2,3-triazole. Purification of themixture by SiO₂ chromatography (EtOAc/hexane) gave Example 24,LC/ESI-MS: m/z 413 (C₂₂H₂₂Cl₂N₄.H⁺) and Example 25, LC/ESI-MS: m/z 413(C₂₂H₂₂Cl₂N₄.H⁺).

EXAMPLE 26

The title compound was prepared according to the procedure of Example22, Step 3, using 26 and 1,2,4-triazole. ESI-MS: m/z=413(C₂₂H₂₂Cl₂N₄.H⁺).

EXAMPLE 27

The title compound was prepared according to the procedure of Example22, Step 3, using 26 and pyrrole. ESI-MS: m/z=411 (C₂₄H₂₄Cl₂N₂.H⁺).

EXAMPLE 28

The title compound was prepared according to the procedure of Example22, Step 3, using 26 and piperidine. ESI-MS: m/z=429 (C₂₅H₃₀Cl₂N₂.H⁺).

EXAMPLE 29

The title compound was prepared according to the procedure of Example22, Step 3, using 26 and morpholine. ESI-MS: m/z=431 (C₂₄H₂₈Cl₂N₂O.H⁺).

EXAMPLES 30 AND 31

To a solution of aminomethylcyclohexane (39 μl, 0.3 mmol) and 5 (72 mg)in THF was added NaBH₃CN (32 mg, 0.5 mmol). The mixture was stirred for˜2 h and then HOAc (60 mg, 1 mmol) was added. The mixture was stirredovernight at rt, water and 1N NaOH were added, and the mixture wasextracted with ether and concentrated. Purification of the residue bySiO₂ chromatography gave Example 30, LC/ESI-MS: m/z 457 (C₂₇H₃₄Cl₂N₂.H⁺)and Example 31, LC/ESI-MS: m/z 457 (C₂₇H₃₄Cl₂N₂.H⁺).

EXAMPLE 32

Step 1:

A mixture of 26 (1.68 g) and lithium azide (225 g) in DMF (5 ml) wasstirred at rt for 24 h, quenched with NH₄Cl (aq.), extracted with EtOAc,dried over Na₂SO₄ and concentrated. Purification of the residue by SiO₂chromatography gave 27. LC/ESI-MS: m/z=387 (C₂₀H₂₀Cl₂N₄.H⁺).

Step 2:

A mixture of 27 (895 mg) and Lindlar catalyst (90 mg) in 1:1 MeOH andEtOAc (20 ml) in the presence of NH₃ in MeOH (2M, 1 ml) was stirredunder H₂ at 1 atm for 2 h. The mixture was filtered and concentrated togive 28. LC/ESI-MS: m/z=361 (C₂₀H₂₂Cl₂N₂.H⁺).

Step 3:

A mixture of 28 (223 mg) and DIPEA (80 mg) in 2-fluoropyridine wasstirred at 130° C. for 36 h. The mixture was concentrated, treated withNH₄Cl (aq.), extracted with EtOAc, dried and concentrated. Purificationof the residue by SiO₂ chromatography gave the title compound (163 mg).ESI-MS: m/z=438 (C₂₅H₂₅Cl₂N₃.H⁺).

EXAMPLE 33

NaH (14 mg, 60% in mineral oil) was added to a solution of 28 (103 mg)in DMF at 0° C. The mixture was warmed to rt, 2-chloropyrimidine (65 mg)was added, and the mixture was heated to 60° C. for 0.5 h, then stirredat rt overnight. The mixture was quenched with NH₄Cl (aq.), extractedwith CH₂Cl₂, dried over Na₂SO₄, filtered and concentrated. Purificationof the residue by SiO₂ preparative thin layer chromatography (20%EtOAc/hexane) gave the title compound (16 mg). LC/ESI-MS: m/z=439(C₂₄H₂₄Cl₂N₄.H⁺).

EXAMPLE 34

A mixture of 28 (328 mg), benzoic acid (122 mg), EDC (175 mg), and HOBT(123 mg) in DMF (2 ml) was stirred at rt overnight. The mixture wasquenched with water, extracted with EtOAc, dried over MgSO₄ andconcentrated. Purification of the residue by SiO₂ chromatography (0˜20%EtOAc/hexane) gave the title compound. LC/ESI-MS: m/z=465(C₂₇H₂₆Cl₂N₂O.H⁺).

EXAMPLE 35

BH₃.THF (1.4 ml, 1M) was added to a solution of Example 34 (258 mg) inTHF. The mixture was stirred at 60° C. overnight. The mixture wasconcentrated, treated with water, extracted with CH₂Cl₂ andconcentrated. Purification of the residue by Gilson HPLC gave the titlecompound (25 mg). LC/ECI-MS: m/z=451 (C₂₇H₂₈Cl₂N₂.H⁺).

EXAMPLE 36

The title compound was prepared according to the procedure of Example22, Step 3, using 26 and piperizine. ESI-MS: m/z=430 (C₂₄H₂₉Cl₂N₃.H⁺).

EXAMPLE 37

A mixture of 25 (56 mg), 2-chloropyrimidine (19 mg) and NaH (16 mg, 60%in mineral oil) in DMF (2 ml) was stirred at 0° C. for 2 h, then at rtfor 3 days. The mixture was quenched with aqueous NH₄Cl, extracted withEtOAc, dried over Na₂SO₄ and concentrated. Purification of the residueby preparative TLC gave the title compound (36 mg). ESI-MS: m/z=440(C₂₄H₂₃Cl₂N₃O.H⁺).

EXAMPLE 38

The title compound was prepared according to the procedure of Example 37using 24, 2-chloropyrimidine and NaH. ESI-MS: m/z=440 (C₂₄H₂₃Cl₂N₃O.H⁺).

EXAMPLE 39

Diethyl azodicarboxylate (111 mg) in THF was added to a mixture of 24(210 mg), phenol (55 mg) and triphenylphosphine (152 mg) in THF. Themixture was stirred at rt overnight. The mixture was concentrated,treated with hexane, filtered and concentrated. Purification of theresidue by SiO₂ chromatography (0˜20% EtOAc/hexane) gave the titlecompound (30 mg). LC/ESI-MS; m/z=438 (C₂₆H₂₅Cl₂NO.H⁺).

EXAMPLE 40

The title compound was prepared according to the procedure of Example 39using 24, p-fluorophenol, diethyl azodicarboxylate, andtriphenylphosphine. LC/ESI-MS; m/z=456 (C₂₆H₂₄Cl₂FNO.H⁺).

EXAMPLE 41

Step 1:

Compound 29 was prepared according to the procedure described in Example2, Step 1, using 6, NaHMDS and 2,3-dibromopyridine. LC/ESI-MS m/z 528(C₂₆H₂₂BrCl₂N₃. H⁺).

Step 2:

The title compound was prepared according to the procedure described inExample 6, Step 2, using 29 and conc. HCl. LC/ESI-MS m/z 503(C₂₅H₂₃BrCl₂N₂.H⁺).

EXAMPLE 42

Step 1:

Compound 30 was prepared according to the procedure described in Example13, Step 1, using 6 and 1-fluoro-4-trifluoromethoxybenzene. LC/ESI-MSm/z 531 (C₂₈H₂₃Cl₂F₃N₂O.H⁺).

Step 2:

The title compound was prepared according to the procedure of Example 8,Step 2, using 30 and LAH. LC/ESI-MS m/z 506 (C₂₇H₂₄Cl₂F₃NO.H⁺).

EXAMPLE 43

Step 1:

A mixture of Example 2 (4 g), Pd(OH)₂/C (12%, 1 g) and ammonium formate(9 g) in MeOH (100 ml) was stirred at reflux for 3 days. The mixture wasfiltered, concentrated, treated with water, extracted with 15%MeOH/CH₂Cl₂, dried over MgSO₄ and concentrated. Purification of theresidue by SiO₂ chromatography (NH₃/MeOH/CH₂Cl₂) gave the title compound(1.5 g). LC/ESI-MS; m/z=189 (C₁₆H₁₂N₂.H⁺).

Step 2:

A mixture of 31 (129 mg),chloro-(2-chlorophenyl)-(2-fluorophenyl)methane (175 mg), K₂CO₃(380 mg)and NaI (103 mg) in CH₃CN (2 ml) was stirred in a sealed tube at 75° C.overnight. The mixture was cooled to rt, treated with CH₂Cl₂, filteredand concentrated. Purification of the residue by SiO₂ chromatography(0˜10% EtOAc/hexane) gave the title compound (84 mg). LC/ESI-MS; m/z=407(C₂₅H₂₄ClFN₂. H⁺).

EXAMPLE 44

The title compound was prepared according to the procedure of Example43, Step 2, using 31, 2,6-dichlorobenzylbromide and K₂CO₃ (508 mg).LC/ESI-MS; m/z=247(C₁₉H₂₀Cl₂N₂.H⁺).

EXAMPLE 45

The title compound was prepared according to the procedure of Example 17using 23 and piperidine. LC/ESI-MS: m/z 457 (C₂₆H₃₀Cl₂N₂O.H⁺).

EXAMPLE 46

The title compound was prepared according to the procedure of Example 17using 23 and 4-fluoroaniline. LC/ESI-MS: m/z 483 (C₂₇H₂₅Cl₂FN₂O.H⁺).

EXAMPLE 47

DMAP (4 mg) was added to a mixture of 23 (43 mg, 0.11 mmol),2-amino-5-fluoropyridine (24.6 mg, 0.58 mmol) and DCC (34 mg, 0.166mmol) in anhydrous CH₂Cl₂ at rt and stirred at rt for 3 days. Themixture was filtered, and the filtrate was washed with water andsaturated aq. NH₄Cl. The organic solution was dried over Na₂SO₄,filtered and concentrated. Purification of the residue by SiO₂chromatography (EtOAc/hexane) gave the title compound (15.5 mg).LC/ESI-MS: m/z 484 (C₂₆H₂₄Cl₂FN₃O.H⁺).

EXAMPLE 48

To PS-EDC resin (45 mg, 0.0615 mmol) in a cartridge was added 23 (8 mg,0.0205 mmol) and HOBt (4.2 mg, 0.031 mmol) in 1 ml CH₃CN-THF (3:2). Asolution of cyclopropanemethylamine in CH₃CN (1 M, 45 μl, 0.045 mmol)was then added to the mixture. The cartridge was capped and shakenovernight. The mixture was treated with PS-isocyanate (40 mg, ˜0.0615mmol), PS-trisamine resins (30 mg, 0.123 mmol) and 0.5 ml CH₃CN-THF(3:2). The cartridge was capped and shaken for 6 h. The mixture wasfiltered and rinsed twice with CH₃CN, and the filtrate was concentratedto give the title compound (6.4 mg). LC/ESI-MS: m/z 443(C₂₅H₂₈Cl₂N₂O.H⁺).

EXAMPLE 49

The title compound was prepared according to the procedure of Example 48using 23 and cyclobutylamine/CH₃CN (1 M). LC/ESI-MS: m/z 443(C₂₅H₂₈Cl₂N₂O.H⁺).

EXAMPLE 50

The title compound was prepared according to the procedure of Example 48using 23 and cyclopentylamine/CH₃CN (1 M). LC/ESI-MS: m/z 457(C₂₆H₃₀Cl₂N₂O.H⁺).

EXAMPLE 51

The title compound was prepared according to the procedure of Example 48using 23 and α-methylbenzylamine/CH₃CN (1 M). LC/ESI-MS: m/z 493(C₂₉H₃₀Cl₂N₂O.H⁺).

EXAMPLE 52

The title compound was prepared according to the procedure of Example 48using 23 and 2-fluorobenzylamine/CH₃CN (1 M). LC/ESI-MS: m/z 497(C₂₈H₂₇Cl₂FN₂O.H⁺).

EXAMPLE 53

The title compound was prepared according to the procedure of Example 48using 23 and 2-S-amino-3-methyl-1-butanol/CH₃CN (1 M). LC/ESI-MS: m/z475 (C₂₆H₃₂Cl₂N₂O₂.H⁺).

EXAMPLE 54

The title compound was prepared according to the procedure of Example 48using 23 and 3-(2-aminoethyl)pyridine/CH₃CN (1 M). LC/ESI-MS: m/z 494(C₂₈H₂₉Cl₂N₃O.H⁺).

EXAMPLE 55

The title compound was prepared according to the procedure of Example 48using 23 and N-(3-aminopropyl)imidazole/CH₃CN (1 M). LC/ESI-MS: m/z 497(C₂₇H₃₀Cl₂N₄O.H⁺).

EXAMPLE 56

To PS-EDC resin (45 mg, 0.0615 mmol) in a cartridge was added 23 (8 mg,0.0205 mmol) in 1 ml CH₃CN-THF (3:2) and HOBT (4.2 mg, 0.031 mmol) inTHF (200 μl). The mixture was shaken at rt for 1 min, and thenbenzylamine/CH₃CN (1 M, 41 μl, 0.041 mmol) was added. The cartridge wascapped and shaken overnight. The mixture was treated with PS-isocyanate(45 mg, 0.0615 mmol), PS-trisamine (40 mg, 0.123 mmol) resins and 0.5 mlCH₃CN-THF (3:2). The cartridge was capped and shaken for 6 h. Themixture was filtered and rinsed twice with CH₃CN. The filtrate wasconcentrated to give the title compound (5.5 mg). LC/ESI-MS: m/z 479(C₂₈H₂₈Cl₂N₂O.H⁺).

EXAMPLE 57

The title compound was prepared according to the procedure of Example 56using 23 and 4-fluorobenzylamine/CH₃CN (1 M). LC/ESI-MS: m/z 497(C₂₈H₂₇Cl₂FN₂O.H⁺).

EXAMPLE 58

The title compound was prepared according to the procedure of Example 56using 23 and pyrrolidine/CH₃CN (1 M). LC/ESI-MS: m/z 443(C₂₅H₂₈Cl₂N₂O.H⁺).

EXAMPLE 59

The title compound was prepared according to the procedure of Example 56using 23 and morpholine/CH₃CN (1 M). LC/ESI-MS: m/z 459(C₂₅H₂₈Cl₂N₂O₂.H⁺).

EXAMPLE 60

The title compound was prepared according to the procedure of Example 18using 23 and 3-aminopyridine. LC/ESI-MS: m/z 466 (C₂₆H₂₅Cl₂N₃O.H⁺).

EXAMPLE 61

A mixture of Example 19 (34 mg) in pyridine/acetic anhydride (1:1) wasstirred at 0° C. overnight and then concentrated. Purification of theresidue by SiO₂ chromatography gave the title compound (13 mg).LC/ESI-MS: m/z 471 (C₂₇H₃₂Cl₂N₂O.H⁺).

EXAMPLE 62

A mixture of Example 19 (40.3 mg, 0.094 mmol), K₂CO₃ (26 mg, 0.188mmole), and 2-bromoethanol (13.3 μl, 0.188 mmol) in DMF was stirred at50° C. for 3 days. The mixture was cooled to rt, quenched with water,and extracted with ether. The organic solution was dried over Na₂SO₄,filtered and concentrated. Purification of the residue by SiO₂chromatography gave the title compound (9.4 mg). LC/ESI-MS: m/z 473(C₂₇H₃₄Cl₂N₂O.H⁺).

EXAMPLE 63

To a solution of 22 in MeOH (75 mg, 0.2 mmol) was added K₂CO₃ (83 mg,0.6 mmol) and tosylmethyl isocyanide (39.1 mg, 0.2 mmol). The mixturewas refluxed under nitrogen for 2 h, cooled to rt and extracted withEtOAc. The organic solution was dried over Na₂SO₄ and concentrated.Purification of the residue by SiO₂ chromatography gave the titlecompound (11.5 mg). LC/ESI-MS: m/z 413 (C₂₃H₂₂Cl₂N₂O.H⁺).

EXAMPLE 64

LAH/THF (1 M, 25 μl) was added to a stirred solution of Example 47 (8mg, 0.0165 mmol) in THF at 0° C. under nitrogen. The mixture was warmedto rt, stirred overnight and H₂O (2 μl), 15% NaOH (6 μl), and H₂O (2 μl)were added sequentially. The mixture was stirred, filtered andconcentrated. Purification of the residue by SiO₂ chromatography gavethe title compound (2.5 mg). LC/ESI-MS: m/z 470 (C₂₆H₂₆Cl₂FN₃.H]⁺).

EXAMPLE 65

NaBH(OAc)₃ (32 mg, 0.15 mmol) was added to a solution of 22 (37.4 mg,0.1 mmol) and 3-aminopyridine (9.6 mg, 0.1 mmol) in CH₂Cl₂ undernitrogen. The mixture was stirred at rt for 3 h, quenched with saturatedNaHCO₃ solution, and extracted with EtOAc. The organic solution wasdried over Na₂SO₄, filtered and concentrated. Purification of theresidue by SiO₂ chromatography gave the title compound (19.5 mg).LC/ESI-MS: m/z 452 (C₂₆H₂₇Cl₂N₃.H⁺).

EXAMPLE 66

The title compound was prepared according to the procedure of Example 65using 22, NaBH(OAc)₃ and 2-aminopyridine. LC/ESI-MS: m/z 452(C₂₆H₂₇Cl₂N₃.H⁺).

EXAMPLE 67

The title compound was prepared according to the procedure of Example 65using 22, NaBH(OAc)₃ and aniline. LC/ESI-MS: m/z 451 (C₂₇H₂₈Cl₂N₂.H⁺).

EXAMPLE 68

Isopropylmagnesium chloride (2M in THF, 500 μl, 1 mmol) was added to asolution of 2-bromopyridine (95.4 μl, 1 mmol) in THF dropwise at rtunder nitrogen. The mixture was stirred at rt for 1.5 h, a solution of22 in THF was added, and the mixture was stirred overnight. The reactionmixture was quenched with water, extracted with CH₂Cl₂, dried overMgSO₄, filtered and concentrated. Purification of the residue by SiO₂chromatography (EtOAc/hexane) gave the title compound (26 mg).LC/ESI-MS: m/z 453 (C₂₆H₂₆Cl₂N₂O.H⁺).

EXAMPLE 69

Phenylmagnesium bromide (1M in THF, 400 μl, 0.4 mmol) was added to asolution of 22 (75 mg, 0.2 mmol) in ether dropwise at −78° C. undernitrogen. The mixture was stirred at −78° C. for 5 h, quenched withsaturated NH₄Cl solution, extracted with ether, dried over Na₂SO₄,filtered and concentrated. Purification of the residue by SiO₂chromatography (EtOAc/hexane) gave the title compound (33.5 mg).LC/ESI-MS: m/z 452 (C₂₇H₂₇Cl₂NO.H⁺).

EXAMPLE 70

A mixture of Example 69 (22 mg, 0.049 mmol) and Dess-Martin periodinane(42 mg, 0.097 mmol) in CH₂Cl₂ was stirred at rt overnight. The mixturewas diluted with ether (4 ml) and poured into a solution of saturatedaqueous NaHCO₃ and sodium thiosulfate (126 mg, in 2 ml). The organicsolution was washed with brine, dried over Na₂SO₄, and concentrated togive the title compound (18.5 mg). LC/ESI-MS: m/z 450 (C₂₇H₂₅Cl₂NO.H⁺).

EXAMPLE 71

Step 1:

Compound 32 was prepared according to the procedure of Example 2, Step1, using 6, NaHMDS and 2-bromo-6-methylpyridine. LC/ESI-MS: m/z 462(C₂₇H₂₅Cl₂N₃.H⁺).

Step 2:

The title compound was prepared according to the procedure of Example 2,Step 2, using 32 and NaOH. LC/ESI-MS: m/z 437 (C₂₆H₂₆Cl₂N₂.H⁺).

EXAMPLE 72

Step 1:

Compound 33 was prepared according to the procedure Example 2, Step 1,using 6, NaHMDS and 2-bromo-4-methylpyridine. LC/ESI-MS: m/z 462(C₂₇H₂₅Cl₂N₃.H⁺).

Step 2:

The title compound was prepared according to the procedure of Example 2,Step 2, using 33 and NaOH. LC/ESI-MS: m/z 437 (C₂₆H₂₆Cl₂N₂.H⁺).

EXAMPLE 73

Step 1:

Compound 34 was prepared according to the procedure Example 2, Step 1,using 6, NaHMDS and 2-bromo-5-methylpyridine. LC/ESI-MS: m/z 462(C₂₇H₂₅Cl₂N₃. H⁺).

Step 2:

The title compound was prepared according to the procedure of Example 2,Step 2, using 34 and NaOH. LC/ESI-MS: m/z 437 (C₂₆H₂₆Cl₂N₂.H⁺).

EXAMPLE 74

Step 1:

Compound 35 was prepared according to the procedure Example 2, Step 1,using 6, NaHMDS and 4-bromo-pyridine (derived from 4-bromo-pyridinehydrobromide). LC/ESI-MS: m/z 448 (C₂₆H₂₃Cl₂N₃.H⁺).

Step 2:

The title compound was prepared according to the procedure of Example 2,Step 2, using 35 and NaOH. LC/ESI-MS: m/z 423 (C₂₅H₂₄Cl₂N₂.H⁺).

The compounds of formula I exhibit greater than 50-fold selectivity overclassical opioid receptors. The NOP receptor shares a high degree ofhomology with classical opioid receptors (i.e., μ, κ and δ), but the NOPreceptor is not activated by endogenous opioids, and endogenous opioidsdo not activate the NOP receptor. Codeine and other opioids used ascough suppressants are known to activate the mu-opioid receptor, causingside effects such as respiratory depression, constipation, tolerance andphysical dependency. NOP receptor agonists do not activate the mu-opioidreceptor, and therefore are expected to result in a superior safetyprofile compared to opioids.

The NOP receptor agonist activity of compounds of formula I, and theireffect on cough and respiration can be measured by the following tests.

Nociceptin Binding Assay

CHO cell membrane preparation expressing the NOP receptor (2 mg) wasincubated with varying concentrations of [¹²⁵I][Tyr¹⁴]nociceptin (3-500pM) in a buffer containing 50 mM HEPES (pH7.4), 10 mM NaCl, 1 mM MgCl₂,2.5 mM CaCl₂, 1 mg/ml bovine serum albumin and 0.025% bacitracin. In anumber of studies, assays were carried out in buffer 50 mM tris-HCl (pH7.4), 1 mg/ml bovine serum albumin and 0.025% bacitracin. Samples wereincubated for 1 h at room temperature (22° C.). Radiolabelled ligandbound to the membrane was harvested over GF/B filters presoaked in 0.1%polyethyleneimine using a Brandell cell harvester and washed five timeswith 5 ml cold distilled water. Nonspecific binding was determined inparallel by similar assays performed in the presence of 1 μM nociceptin.All assay points were performed in duplicates of total and non-specificbinding.

Calculations of Ki were made using methods well known in the art.

For compounds of this invention, Ki values were determined to be in therange of about 1 to about 500 nM, with compounds having a Ki value lessthan 10 nM being preferred.

Using the procedures described the European Journal of Pharmacology, 336(1997), p. 233-242, the agonist activity of compounds of the inventionis determined.

Cough Studies

The effects of a nociceptin agonist are evaluated in capsaicin-inducedcough in the guinea pig according to the methods of Bolser et al.British Journal of Pharmacology (1995) 114, 735-738 (also see McLeod etal, British Journal of Pharmacology (2001) 132, 1175-1178). This modelis a widely used method to evaluate the activity of potentialantitussive drugs. Overnight fasted male Hartley guinea pigs (350-450 g,Charles River, Bloomington, Mass., USA) are placed in a 12″×14″transparent chamber. The animals are exposed to aerosolized capsaicin(300 μM, for 4 min) produced by a jet nebulizer (Puritan Bennett,Lenexa, Kans., USA) to elicit the cough reflex. Each guinea pig isexposed only once to capsaicin. The number of coughs are detected by amicrophone placed in the chamber and verified by a trained observer. Thesignal from the microphone is relayed to a polygraph which provides arecord of the number of coughs. Either vehicle (methylcellulose 1 ml/kg,p.o.) or test compound is given 2 hours before aerosolized capsaicin.The antitussive activity of baclofen (3 mg/kg, p.o.) is also tested as apositive control.

Respiratory Measurements

Studies are performed on male Hartley guinea pigs ranging in weight from450 to 550 g. The animals are fasted overnight but given water andlibitum. The guinea pigs are placed in a whole-body, head-outplethysmograph and a rubber collar is placed over the animal's head toprovide an airtight seal between the guinea pig and the plethysmograph.Airflow is measured as a differential pressure across a wire mesh screenwhich covers a 1-in hole in the wall of the plethysmograph. The airflowsignal is integrated to a signal proportional to volume using apreamplifier circuit and a pulmonary function computer (BuxcoElectronics, Sharon, Conn., model XA). A head chamber is attached to theplethysmograph and air from a compressed gas source (21% O₂, balance N₂)is circulated through the head chamber for the duration of study. Allrespiratory measurements are made while the guinea pigs breathe thiscirculating air.

The volume signal from each animal is fed into a dataacquisition/analysis system (Buxco Electronics, model XA) thatcalculates tidal volume and respiratory rate on a breath-by-breathbasis. These signals are visually displayed on a monitor. Tidal volumeand respiratory rate are recorded as an average value every minute.

The guinea pigs are allowed to equilibrate in the plethysmograph for 30min. Baseline measurements are obtained at the end of this 30 minperiod. The guinea pigs are then removed from the plethysmograph andorally dosed with test compound (10 mg/kg, p.o.), baclofen (3 mg/kg,p.o.) or a methylcellulose vehicle placebo (2 ml/kg, p.o.). Immediatelyafter dosing, the guinea pigs are placed into the plethysmograph, thehead chamber and circulating air are reconnected and respiratoryvariables (tidal volume (V_(T)), respiratory rate (f) and minute volume(MV=V_(T)×f)) are measured at 30, 60, 90 and 120 min post treatment.This study is performed under ACUC protocol #960103.

One to three compounds of formula I can be administered in the methodsof this invention, preferably one.

Compounds of this invention exhibit anti-tussive activity, making themuseful for suppressing coughing in mammals. For mammals treated forcoughing, at least one nociceptin receptor NOP agonist of formula I maybe administered along with one or more additional agents for treatingcough, allergy or asthma symptoms selected from antihistamines,5-lipoxygenase inhibitors, leukotriene inhibitors, H₃ inhibitors,β-adrenergic receptor agonists, xanthine derivatives, α-adrenergicreceptor agonists, mast cell stabilizers, anti-tussives, expectorants,NK₁, NK₂ and NK₃ tachykinin receptor antagonists, and GABA_(B) agonists.Preferably a combination of this invention comprises one compound offormula I and 1-3 additional agents, preferably 1-2 additional agents,and more preferably 1 additional agent.

Non limitative examples of antihistamines include: astemizole,azatadine, azelastine, acrivastine, brompheniramine, cetirizine,chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine,carbinoxamine, descarboethoxyloratadine (also known as SCH-34117),doxylamine, dimethindene, ebastine, epinastine, efletirizine,fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine,mizolastine, equitazine, mianserin, noberastine, meclizine,norastemizole, picumast, pyrilamine, promethazine, terfenadine,tripelennamine, temelastine, trimeprazine and triprolidine.

Non-limitative examples of histamine H₃ receptor antagonists include:thioperamide, impromidine, burimamide, clobenpropit, impentamine,mifetidine, S-sopromidine, R-sopromidine, SKF-91486, GR-175737, GT-2016,UCL-1199 and clozapine. Other compounds can readily be evaluated todetermine activity at H₃ receptors by known methods, including theguinea pig brain membrane assay and the guinea pig neuronal ileumcontraction assay, both of which are described in U.S. Pat. No.5,352,707. Another useful assay utilizes rat brain membranes and isdescribed by West et al., “Identification of Two-H₃-Histamine ReceptorSubtypes,” Molecular Pharmacology, Vol. 38, pages 610-613 (1990).

The term “leukotriene inhibitor” includes any agent or compound thatinhibits, restrains, retards or otherwise interacts with the action oractivity of leukotrienes. Non-limitative examples of leukotrieneinhibitors include montelukast[R-(E)]-1[[[1-[3-[2-(7-chloro-2-quinolinyl)-ethenyl]phenyl]-3[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]-methyl]cyclo-propaneaceticacid and its sodium salt, described in EP 0 480 717;1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)-phenyl)thio)methylcyclopropaneacetic acid, and its sodium salt, described in WO97/28797 and U.S. Pat. No. 5,270,324;1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]-pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio) methyl)cyclopropaneacetic acid, and its sodium salt,described in WO 97/28797 and U.S. Pat. No. 5,472,964; pranlukast,N-[4-oxo-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-8-yl]-p-(4-phenylbutoxy)benzamide)described in WO 97/28797 and EP 173,516; zafirlukast,(cyclopentyl-3-[2-methoxy-4-[(o-tolylsulfonyl)carbamoyl]benzyl]-1-methyl-indole-5-carbamate) described in WO 97/28797and EP 199,543; and[2-[[2(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid, described in U.S. Pat. No. 5,296,495 and Japanese patentJP08325265 A.

The term “5-lipoxygenase inhibitor” or “5-LO inhibitor” includes anyagent or compound that inhibits, restrains, retards or otherwiseinteracts with the enzymatic action of 5-lipoxygenase. Non-limitativeexamples of 5-lipoxygenase inhibitors include zileuton, docebenone,piripost, ICI-D2318, and ABT 761.

Non-limitative examples of β-adrenergic receptor agonists include:albuterol, bitolterol, isoetharine, metaproterenol, pirbuterol,salmeterol, terbutaline, isoproterenol, ephedrine and epinephrine.

A non-limitative example of a xanthine derivative is theophylline.

Non-limitative examples of α-adrenergic receptor agonists includearylalkylamines, (e.g., phenylpropanolamine and pseudephedrine),imidazoles (e.g., naphazoline, oxymetazoline, tetrahydrozoline, andxylometazoline), and cycloalkylamines (e.g., propylhexedrine).

A non-limitative example of a mast cell stabilizer is nedocromil sodium.

Non-limitative examples of anti-tussive agents include codeine,dextromethorphan, benzonatate, chlophedianol, and noscapine.

A non-limitative example of an expectorant is guaifenesin.

Non-limitative examples of NK₁, NK₂ and NK₃ tachykinin receptorantagonists include CP-99,994 and SR 48968.

Non-limitative examples of GABA_(B) agonists include baclofen and3-aminopropyl-phosphinic acid.

Compounds of this invention are useful in treating UI or overactivebladder in mammals. At least one compound of formula I may beadministered along with one or more additional agents for treating UI oroveractive bladder. Agents known to treat UI or overactive bladderinclude muscarinic antagonists, for example darifenacin, tolterodine,solifenacin, trospium, duloxetine and temiverine, and antispasmodicand/or anticholinergic agents such as oxybutynin and hyoscyamine.Preferably a combination of this invention comprises one compound offormula I and 1 additional agent.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably a compound of this invention is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound of formula I in a unit dose ofpreparation may be varied or adjusted from about 0.1 mg to 1000 mg, morepreferably from about 1 mg. to 300 mg, according to the particularapplication.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen is oral administration of from 10 mg to 2000 mg/daypreferably 10 to 1000 mg/day, in two to four divided doses to providerelief from pain, anxiety, depression, asthma or alcohol abuse. Thecompounds are non-toxic when administered within this dosage range.

When the NOP agonist of formula I is administered in combination withone or more additional agents, the compound of formula I and theadditional agent(s) are preferably administered in a combined dosageform (e.g., a single tablet), although they can be administeredseparately. The additional agents are administered in amounts effectiveto provide relief from cough, allergy or asthma symptoms, preferablyfrom about 0.1 mg to 1000 mg, more preferably from about 1 mg to 300 mgper unit dose. A typical recommended dosage regimen of the additionalagent is from 1 mg to 2000 mg/day, preferably 1 to 1000 mg/day, in twoto four divided doses. Typical dosage amounts of the other agents may bedetermined from the literature, for example in The Physicians's DeskReference.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound represented by the formula

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ isR⁴-aryl, R⁴-arylalkyl, R⁴-heteroaryl, R⁴-heteroarylalkyl, R⁴-cycloalkyl,R⁴-cycloalkylalkyl, R⁴-heterocycloalkyl or R⁴-heterocycloalkylalkyl; R²is R⁵-aryl, R⁵-arylalkyl, R⁵-heteroaryl, R⁵-heteroarylalkyl,R⁵-cycloalkyl, R⁵-cycloalkylalkyl, R⁵-heterocycloalkyl orR⁵-heterocycloalkylalkyl; R³ is R⁶-alkyl, R⁶-aryl, R⁶-heteroaryl,R⁶-cycloalkyl or R⁶-heterocycloalkyl; X is a bond, (C₁-C₃)alkylene,—(CH₂)_(m)—N(R⁷)—(CH₂)_(n)—, —(CH₂)_(m)—O—(CH₂)_(n)—,—(CH₂)_(m)—S—(CH₂)_(n)—, —C(O)—, —CH(OH)—, —C(O)N(R⁷)—,—C(O)N(R⁷)-alkylene or —N(R⁷)C(O)—; n is 0, 1, 2, 3; 4, 5 or 6; m is 0,1, 2, 3; 4, 5 or 6; provided that the sum of m and n is 0, 1, 2, 3; 4, 5or 6; each R⁴ and R⁵ is 1 to 3 substituents independently selected fromthe group consisting of H, halo, alkyl, cycloalkyl, —CN, —CF₃,—(CH₂)_(p)—OR⁸, —N(R¹⁰)₂ and —(CH₂)_(n)—N(R¹⁰)₂; R⁶ is 1 to 3substituents independently selected from the group consisting of H,halo, alkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, —CN,cyanoalkyl, —CF₃, —C(O)alkyl, —(CH₂)_(p)—OR⁸, —COOR⁸, —N(R¹⁰)₂,—(CH₂)_(n)—N(R¹⁰)₂ and —C(O)N(R¹⁰)₂; p is 0, 1, 2, 3; 4, 5 or 6; R⁷ is Hor alkyl; R⁸ and R⁹ are independently selected from the group consistingof H, alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, alkoxyalkyl,aminoalkyl, alkyl-C(O)— and alkyl-C(O)—N(R⁷)—C(O)—; and R¹⁰ isindependently selected from the group consisting of H and alkyl.
 2. Acompound of claim 1 wherein R¹ is R⁴-phenyl and R² is R⁵-phenyl, whereinR⁴ and R⁵ are independently selected from the group consisting of H,halo and alkyl.
 3. A compound of claim 2 wherein R¹ is R⁴-phenyl whereinR⁴ is one halo atom, and R² is R⁵-phenyl wherein R⁵ is one halo atom. 4.A compound of claim 3 wherein R⁴ and R⁵ are chlorine.
 5. A compound ofclaim 1 wherein X is a bond, —N(R⁷)—(CH₂)_(n)— wherein R⁷ is H and n is0 or 1, or —C(O)N(R⁷)— wherein R⁷ is H.
 6. A compound of claim 5 whereinX is a bond.
 7. A compound of claim 1 wherein R³ is R⁶-aryl,R⁶-heteroaryl or R⁶-heterocycloalkyl.
 8. A compound of claim 7 whereinR³ is R⁶-phenyl, R⁶-pyridyl, R⁶-pyrimidyl, R⁶-imidazolyl,R⁶-benzimidazolyl, R⁶-piperidinyl or R⁶-morpholinyl.
 9. A compound ofclaim 8 wherein R⁶ is one substituent selected from the group consistingof H, halo, alkyl, OH and —OCH₃.
 10. A compound of claim 1 selected fromthe group consisting of


11. The compound having the formula


12. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 in combination with a pharmaceuticallyacceptable carrier.
 13. A pharmaceutical composition comprising: atherapeutically effective amount of a compound of claim 1; atherapeutically effective amount of one or more additional agentsselected from the group consisting of: antihistamines, 5-lipoxygenaseinhibitors, leukotriene inhibitors, H₃ inhibitors, β-adrenergic receptoragonists, xanthine derivatives, α-adrenergic receptor agonists, mastcell stabilizers, anti-tussives, expectorants, NK₁, NK₂ and NK₃tachykinin receptor antagonists; GABA_(B) agonists, muscarinicantagonists, anticholinergic agents and antispasmodic agents; and apharmaceutically acceptable carrier.
 14. A method of treating cough,pain, anxiety, asthma, depression, alcohol abuse, urinary incontinenceor overactive bladder comprising administering an effective amount of acompound of claim 1 to a mammal in need of such treatment.
 15. Themethod of claim 14, wherein said method is for treating cough.
 16. Themethod of claim 15, further comprising administering 1-3 additionalagents selected from the group consisting of: antihistamines,5-lipoxygenase inhibitors, leukotriene inhibitors, H₃ inhibitors,β-adrenergic receptor agonists, xanthine derivatives, α-adrenergicreceptor agonists, mast cell stabilizers, anti-tussives, expectorants,NK₁, NK₂ and NK₃ tachykinin receptor antagonists, and GABA_(B) agonists.17. The method of claim 14, wherein said method is for treating urinaryincontinence or overactive bladder.
 18. The method of claim 17, furthercomprising administering an agent selected from the group consisting ofmuscarinic antagonists, anticholinergic agents and antispasmodics. 19.The method of claim 18, wherein said agent is selected from the groupconsisting of darifenacin, tolterodine, solifenacin, trospium,duloxetine, temiverine, oxybutynin and hyoscyamine.